Axon injury is, unfortunately, common and of enormous consequence to public health. For example, the paralysis pursuant to trauma to the spinal cord is a direct result of the interruption of axons running longitudinally in the cord; the inability of these axons to regenerate renders the paralysis effectively permanent. The cell body from which a transected axon arises displays electrical and biochemical changes in response to the injury that underlie degenerative, protective and regenerative responses of the cell, since it is in the cell body that the proteins for the neuron are manufactured. The work in this project seeks to help define the molecular events occurring in the cell body that underlie the response to axotomy. The work will focus on early events in the nucleus that could trigger or orchestrate subsequent degenerative, protective or regenerative responses. Preliminary screening experiments using a giant invertebrate neuron have detected a few nuclear proteins which respond rapidly and particularly strongly to axotomy. One of these may be a known gene-regulatory protein, CREB. Work in this project is designed to follow up this lead by confirming the identification of CREB and determining whether a related gene-regulatory factor (AP-1) also responds to axotomy and determining the mode of regulation of CREB. Also, through the use of a technique that blocks the functioning of CREB or AP-1, it will be determined whether CREB or AP-1 functioning is necessary for certain important responses of the neuron to axotomy, such as the overall increase in protein and RNA synthesis or the increase in production of specific proteins involved in growth. The knockout technique capitalizes on the enormous size of certain Aplysia neurons. Work is also designed to determine whether mammalian peripheral and/or central neurons display an early CREB response and whether the response is correlated with the regenerative potential of the neuron.